EP3630166B1 - Rapid-acting insulin compositions - Google Patents

Rapid-acting insulin compositions Download PDF

Info

Publication number
EP3630166B1
EP3630166B1 EP18735017.8A EP18735017A EP3630166B1 EP 3630166 B1 EP3630166 B1 EP 3630166B1 EP 18735017 A EP18735017 A EP 18735017A EP 3630166 B1 EP3630166 B1 EP 3630166B1
Authority
EP
European Patent Office
Prior art keywords
insulin
triphosphate
formulation
pharmaceutical composition
concentration
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP18735017.8A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP3630166A1 (en
Inventor
Chad Donald Paavola
Jun Zhang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP3630166A1 publication Critical patent/EP3630166A1/en
Application granted granted Critical
Publication of EP3630166B1 publication Critical patent/EP3630166B1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention is a pharmaceutical insulin composition for parenteral injection to counteract prandial and post-prandial blood glucose excursions.
  • the composition includes an insulin and triphosphate, and has faster uptake of insulin from injection sites than existing commercial insulin compositions.
  • the composition is useful for rapidly providing insulin activity when insulin is needed, e.g., when food is consumed.
  • Diabetes mellitus is a chronic disorder characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.
  • Type 1 diabetes mellitus is characterized by little or no insulin secretory capacity, and patients with type 1 diabetes mellitus require insulin for survival.
  • type 2 diabetes mellitus the combined effects of impaired insulin secretion and insulin resistance result in elevated blood glucose levels. In at least one-third of patients with type 2 diabetes mellitus the disease progresses to an absolute requirement for insulin therapy.
  • the time-action profile of insulin is important for controlling post-prandial blood glucose levels.
  • the pancreas secretes a spike of insulin in response to absorbed food, which results in increased blood insulin levels within several minutes.
  • insulin In individuals with type 1 diabetes and in certain individuals with type 2 diabetes, insulin must be administered. However, administered insulin enters the blood more slowly than endogenously secreted insulin, and slow onset may result in hyperglycemia during the early postprandial period. Too long duration of action can result in excessive insulin between meals which results in late postprandial hypoglycemia and/or weight gain.
  • US2014/0378383 discloses insulin compositions containing a combination of a substituted anionic compound consisting of a saccharide backbone formed from between 1 and 8 hexose saccharide units having partially substituted carboxyl functional groups with a polyanionic compound, and states that such a combination makes it possible to accelerate the passage of the insulin into the blood.
  • US2015/0231160 discloses insulin compositions containing a combination of an oligosaccharide and a polyanionic compound, and states this combination allows a significant reduction in the time for the start of action of a formulation of rapid-acting insulin analog.
  • compositions containing triphosphate which contain triphosphate but do not also contain either a substituted anionic compound, as that term is used in US2014/0378373 , or an oligosaccharide, as described in US2015/0231160 , and no data are provided on the pharmacokinetics or pharmacodynamics of compositions containing triphosphate or any other polyphosphoric acid.
  • US2014357554 and US2015273022 describe compositions said to have rapid onset of insulin action which contain EDTA, citrate, and magnesium containing compounds, one example of which is magnesium pyrophosphate. The magnesium compound is stated to minimize injection site irritation "but not change the rate of subcutaneous absorption," and no data on compositions containing magnesium pyrophosphate are described.
  • compositions of insulin intended for use at meal-time, that have more rapid uptake of insulin from the injection site and more rapid onsets of action than existing commercial insulin products.
  • the present invention seeks to meet these needs by providing pharmaceutically-acceptable, formulations of insulin that have more rapid uptake of insulin into the blood and more rapid onset of action than existing commercial insulin products.
  • a pharmaceutical composition comprising an insulin and triphosphate in a concentration of about 10 to about 30 mM, provided that the composition does not contain either a saccharide multimer or EDTA.
  • the concentration of triphosphate is about 20 to about 25 mM. In certain embodiments, the concentration of triphosphate is selected from the group consisting of 10, 15, 20, 25 or 30 mM.
  • the composition further comprises zinc.
  • the zinc concentration is from about 0.2 to about 5 mM.
  • the composition further comprises a tonicity agent.
  • the tonicity agent is glycerol.
  • the composition further comprises one or more preservatives.
  • the one or more preservatives are selected from the group consisting of phenol, meta-cresol, and benzyl alcohol.
  • the insulin is selected from the group consisting of human insulin, insulin lispro, insulin aspart and insulin glulisine. In certain embodiments, the insulin concentration is from about 40 to about 500 IU/mL. In certain embodiments, the insulin concentration is from about 100 to about 200 IU/mL.
  • compositions for use as a medicament there is provided one of the above-described compositions for use as a medicament.
  • compositions for use in the treatment of diabetes there is provided one of the above-described compositions for use in the treatment of diabetes.
  • an article of manufacture comprising one of the above-described compositions.
  • the article of manufacture is a multi-use vial.
  • the article of manufacture is a pre-filled, disposable pen.
  • the article of manufacture is a re-usable pen.
  • the article of manufacture is an autoinjector.
  • the article of manufacture is a pump for continuous subcutaneous insulin infusion (CSII).
  • CSII continuous subcutaneous insulin infusion
  • saccharide multimer means any compound containing more than one saccharide unit bound together, including for example the substituted anionic compounds described in US2014/0378383 and the oligosaccharides described in US2015/0231160 .
  • the term "does not contain a saccharide multimer or EDTA” means that the composition contains no saccharide multimers or EDTA, or contains only a de minimis quantity of saccharide multimers or EDTA such that the time action profile of the insulin is unaffected.
  • insulin means human insulin or a structural variant, mutant, or analog of human insulin that has the functional activity of human insulin.
  • Analogs of human insulin include but are not limited to insulin lispro, insulin aspart, and insulin glulisine, or other "rapid-acting" insulin analogs.
  • Insulin for commercial products may be produced using recombinant DNA methods or by chemical synthesis. Recombinant methods are well-known and are strongly preferred.
  • a molecule of human insulin ( CAS No. 11061-68-0 ) consists of two amino acid chains, A and B, whose sequences are well-known. The chains are joined by two disulfide bonds: CysA7-CysB7 and CysA20-CysB19.
  • the A-chain has an intra-chain disulfide bond at CysA6-CysA11.
  • the human insulin A-chain has the following sequence of amino acids: Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Asn Tyr Cys Asn (SEQ ID NO:1)
  • the human insulin B-chain has the following sequence of amino acids: Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr (SEQ ID NO: 2).
  • Insulin lispro ( CAS No. 133107-64-9 ), the drug substance in HUMALOG ® , has been shown to be equipotent to human insulin on a molar basis but its effect after subcutaneous injection is more rapid and of shorter duration than that of injected soluble human insulin. A consistent pattern of kinetics with a shorter Tmax and half-life and with a higher Cmax was observed for insulin lispro when compared to the human insulin. Insulin lispro is biologically equivalent to insulin in several in vitro tests including insulin receptor binding in cultured lymphocytes, human placenta and human liver, and glucose transport in adipocytes.
  • HUMALOG ® contains m-cresol as a preservative and a stabilizer, a tonicity modifier (glycerin), a buffering agent (dibasic sodium phosphate), a stabilizer (zinc oxide) and pH adjustment for the vehicle.
  • a molecule of insulin lispro consists of the human insulin A-chain cross-linked with the insulin lispro B-chain, whose amino acid sequence is given by SEQ ID NO:3, below: Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Lys Pro Thr (SEQ ID NO: 3).
  • One unit of insulin lispro is equivalent to 0.0347mg insulin lispro.
  • Insulin aspart ( CAS No. 116094-23-6 ), the drug substance in NOVOLOG ® , is another rapid-onset insulin analog. Its structure consists of the A-chain of human insulin and a B-chain analog as reflected in the following amino acid sequence: Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Asp Lys Thr (SEQ ID NO: 4).
  • One unit of insulin aspart corresponds to 6 nmol, corresponding with 0.035 mg salt-free anhydrous insulin aspart.
  • Insulin glulisine (CAS No. 207748-29-6 ), the drug substance in APIDRA ® , is yet another rapid-onset insulin analog.
  • a molecule of insulin glulisine consists of human insulin A-chain and a modified B-chain compared with human insulin, as reflected in the following amino acid sequence: Phe Val Lys Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Glu Thr (SEQ ID NO: 5).
  • One unit of insulin glulisine corresponds approximately to 0.0349 mg of insulin glulisine.
  • compositions of the present invention have concentrations of insulin between 0.24 and 3 mM (40 - 500 IU/mL; 1.4 mg/mL - 17.5 mg/mL).
  • concentrations of insulin between 0.24 and 3 mM (40 - 500 IU/mL; 1.4 mg/mL - 17.5 mg/mL).
  • the compositions of the present invention are likely to have specific concentrations of 40, 100, 200, 300, 400, and 500 IU/mL (1.4, 3.5, 7, 10.5, 14, and 17.5 mg/mL).
  • Preferred concentrations are 100 and 200 IU/mL.
  • Polyphosphates are inorganic, multi-charged, polyvalent anions consisting of 2 or more phosphate groups covalently bonded via P-O-P bonds. They are widely used in detergents, foods, cosmetics, and biomedical applications as chelating agents, buffers, and cross-linking agents, among other uses.
  • a number of polyphosphates are "generally regarded as safe" by the U.S. Food and Drug Administration for use in foods ("GRAS”), including for example those listed in Table 1 below. Table 1. Examples of GRAS polyphosphates. GRAS Substance Formula (m.w.) CAS No.
  • Triphosphate has been used as a cross-linking agent in polymer-based nanocarriers, especially chitosan-based nanocarriers, for oral, nasal, parenteral, or transdermal delivery of a large range of medically-important payloads, such as antigens, anti-cancer drugs, genetic materials, and proteins, including insulins.
  • medically-important payloads such as antigens, anti-cancer drugs, genetic materials, and proteins, including insulins.
  • Kouchak, et al. "Effect of different molecular weights of chitosan on preparation and characterization of insulin loaded nanoparticles by ion gelation method," 4 Internat'l J. Drug Dev. & Res. 271 (2012 ).
  • such carriers are not directed towards accelerating the time action profile of administered insulin.
  • the polyphosphates shown herein to be useful for increasing the rate of insulin absorption from injection sites are pyrophosphate (diphosphate, [O 3 -P-O-P-O 3 ] -4 , P 2 O 7 ) and triphosphate ([O 3 -P-O-(PO 2 )-O-P-O 3 ] -5 , P 3 O 10 ).
  • the effects on insulin absorption are believed to be provided by these polyphosphates as well as trimetaphosphate (P 3 O 9 )- and tetraphosphate (P 4 O 13 -6 ).
  • the particular polyphosphate compound used may be the acidic form or various salt forms, especially the alkali (e.g., sodium and potassium) salts.
  • Triphosphate, and its various salts, especially their alkali (e.g., sodium and potassium) and alkaline earth metal (e.g., calcium and magnesium) salts may be used in the present invention.
  • the concentration of triphosphate in the compositions is in the range of 10 mM to 30 mM. Certain compositions have triphosphate concentrations in the range of 15 mM to 25 mM.
  • compositions have about 2.4 atoms of zinc per six molecules of insulin (HUMULIN ® R U-500), and some have about 3.0 atoms of zinc per six molecules of insulin (HUMALOG ® , NOVOLOG ® ).
  • Certain embodiments of the present invention include zinc in a concentration sufficient to provide between about 2-4 zinc atoms per six molecules of insulin.
  • Other embodiments include zinc in a concentration of up to about 5 mM.
  • the concentration of zinc ranges from about 0.2 to about 5 mM.
  • the concentration of zinc ranges from about 0.5 to about 2 mM.
  • the concentration of zinc is selected from the group consisting of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.3 and 2 mM.
  • compositions are sterile when first produced.
  • an anti-microbial preservative compound or mixture of compounds that is compatible with the other components of the formulation is typically added at sufficient strength to meet regulatory and pharmacopoeial anti-microbial preservative requirements. See U.S. Pharmacopeia Monographs. Insulin lispro injection. USP29-NF24; British Pharmacopeia Monographs 2008 Volume III: Insulin aspart injection; U.S. Pharmacopeia Monographs. Insulin assays; and U.S. Pharmacopeia general chapters. USP29-NF24. Rockville, MD: U.S. Pharmacopeial Convention; 2005. Antimicrobial effectiveness testing; pp. 2499-2500.
  • Preferred preservatives are aryl acids and phenolic compounds, or mixtures of such compounds.
  • Preservatives most commonly used in insulin products are phenol, m-cresol, and benzyl alcohol. Effective concentrations can be ascertained readily using the methods referenced above.
  • Present commercial compositions contain 3.15 mg/mL m-cresol (HUMALOG ® and APIDRA ® )), 1.72 mg/mL m-cresol and 1.50 mg/mL phenol (NOVOLOG ® ), and 2.5 mg/mL m-cresol (HUMULIN ® R U-500).
  • the pH of insulin compositions of the present invention is typically 7.0 to 7.8 and it is adjusted using physiologically appropriate acids and bases, typically hydrochloric acid 10% and sodium hydroxide 10%.
  • the pH for commercial insulin formulations is usually in the range 7.2 to 7.6, with 7.4 ⁇ 0.1 as a common target pH.
  • compositions be approximately isotonic with body fluids at the sites of injection.
  • a tonicity agent should generally be added to raise the tonicity of the composition to about 300 mOsmol/kg.
  • Typical tonicity agents are glycerol (glycerin) and sodium chloride. The amount of tonicity agent to add is readily determined using standard techniques. Remington: The Science and Practice of Pharmacy, David B. Troy and Paul Beringer, eds., Lippincott Williams & Wilkins, 2006, pp. 257-259 ; Remington: Essentials of Pharmaceutics, Linda Ed Felton, Pharmaceutical Press, 2013, pp. 277-300 .
  • compositions of the present invention are typically administered subcutaneously, either in multiple daily injections (MDI) from a pre-filled, disposable pen, reusable pen, automatic pen injector, multi-use vial or a pump for CSII.
  • MDI daily injections
  • diabetic Fifteen diabetic (alloxan induced), castrated, male Yucatan miniature swine (average age 17 months old and average body weight 40 kgs) with previously fitted vascular access ports are used.
  • the diabetic animals are housed individually and have ad lib access to fresh water at all times. They are fed two meals per day of house diet S-9 and receive appropriate maintenance basal and prandial insulin twice per day to manage their diabetic condition.
  • Test articles are formulated and shipped overnight on cold packs to the study site. They are stored refrigerated until time of dosing and then returned to the refrigerator after dosing of all animals was complete. During the dosing period the test articles remain in an insulated box when not being withdrawn from. HUMALOG ® insulin control is from a commercial vial. Table 2. Compositions of test and control articles.
  • Formulation Composition HUMALOG 3.5 mg/mL insulin lispro 7 mM sodium phosphate 0.3 mM 3.15 mg/mL m-cresol 16 mg/mL glycerin pH 7.4 insulin lispro + 25 mM Pyrophosphate
  • Reference Formulation A 92 U/mL insulin lispro (3.2 mg/mL) 7 mM sodium phosphate 0.3 mM zinc 3.15 mg/mL m-cresol 6.33 mg/mL glycerin 25 mM sodium pyrophosphate pH 7.4 insulin lispro + 25 mM Triphosphate
  • Formulation B 94 U/mL insulin lispro (3.3 mg/mL) 7 mM sodium phosphate 0.3 mM zinc 3.15 mg/mL m-cresol 4.49 mg/mL glycerin 25 mM sodium triphosphate pH 7.4
  • the study is designed as a three-way cross-over design. This design allows for each individual animal to receive each of the three test articles by dosing one test article each study date (3 dates each 7 days apart). The day prior to study, animals are fed half their daily ration and received 0.2 U/kg Humalog Mix 75/25 Insulin at their morning maintenance administration. All study animals are food-fasted overnight and do not receive their evening insulin or meal prior to drug administration on study day.
  • the animals are returned to their pens and fed ⁇ 300 g S-9 diet. Twenty minutes after the presentation of the fully consumed meal, the animals are injected with test article subcutaneously in the flank (0 min) with a Terumo insulin syringe (0.5 ml 1/2" needle). Dosing involves a single injection of 0.2 U/kg of insulin activity. All study animals have ad libitum access to clean, fresh water throughout the remaining blood collection period.
  • Serial blood samples (2.0 mL each) are collected from each animal at the following time points: -30, -20 (then immediately Fed), 0 (just before dose), 5, 10, 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 240, and 360 minutes following the SC dosing.
  • Blood samples (anticoagulant: none [serum]) are maintained at ambient temperature for at least 30 minutes but no more than 2 hours to allow for clotting. Serum is then separated by centrifugation and divided into two aliquots and stored frozen at approximately -70 °C.
  • Serum insulin concentrations are determined using a competitive radioimmunoassy (RIA).
  • RIA competitive radioimmunoassy
  • serum insulin displaced 1251-insulin for binding to guinea pig anti-rat insulin.
  • the antibody complex is precipitated with a goat anti-guinea pig IgG serum reagent.
  • the upper and lower limits of quantitation of the RIA are 5000 and 20 pM, respectively, in heat-treated charcoal-stripped serum.
  • Non-compartmental pharmacokinetic analysis is performed using Phoenix WinNonLin 6.3. Values below the lower limit of quantitation are assigned a value of 20 pM for calculations.
  • the PK/PD data demonstrate that pyrophosphate or triphosphate accelerated time-action and reduced Tmax as compared with HUMALOG.
  • Reference Formulation A with pyrophosphate had Tmax that was ⁇ 47% faster than HUMALOG ( ⁇ 33% faster by median Tmax) and had a comparable mean Cmax to HUMALOG.
  • Formulation B with triphosphate had ⁇ 77% faster mean Tmax than HUMALOG ( ⁇ 67% faster in median Tmax) and ⁇ 125% higher Cmax than Humalog.
  • Formulations containing 25 mM pyrophosphate or 25 mM triphosphate caused faster Tmax and higher Cmax as compared with HUMALOG.
  • diabetic Alloxan induced
  • castrated, male Yucatan miniature swine average age 14 mos old and average body weight 35 kgs
  • the diabetic animals are housed individually and have ad lib access to fresh water at all times. They are fed two meals per day of house diet S-9 and receive appropriate maintenance basal and prandial insulin twice per day to manage their diabetic condition.
  • Test articles are formulated and shipped overnight on cold packs. They are stored refrigerated until time of dosing and then returned to the refrigerator after dosing of all animals was complete. During the dosing period the test articles remained in an insulated box when not being withdrawn from.
  • HUMALOG control is a commercial vial. Table 5. Compositions of test and control articles.
  • Formulation Name Formulation Composition HUMALOG 3.5 mg/mL insulin lispro 7 mM sodium phosphate, pH 7.4 0.3 mM Zn molecules 16 mg/mL glycerin 3.15 mg/mL m-cresol Reference Formulation C: insulin lispro + 5 mM triphosphate
  • Formulation D insulin lispro + 10 mM triphosphate 3.5 mg/mL insulin lispro 7 mM sodium phosphate 0.3 mM zinc 13.70 mg/mL glycerin 3.15 mg/mL m-cresol 5 mM sodium triphosphate, pH 7.4 3.5 mg/mL insulin lispro 7 mM sodium phosphate 0.3 mM zinc 11.40 mg/mL glycerin 3.15 mg/mL m-cresol 10 mM sodium triphosphate, pH 7.4 Formulation E: insulin lispro + 20 mM triphosphate 3.5 mg/mL insulin lispro 7 mM sodium phosphate
  • the study is designed a four-way cross over design allowing for each individual animal to receive each of the three test articles and the control by dosing one test article on each study date (4 dates each, 7 days apart).
  • the animals are returned to their pens and fed ⁇ 300 g S-9 diet. Twenty minutes after the presentation of the fully consumed meal, the animals are injected with test article subcutaneously in the flank (0 min) with a Terumo insulin syringe (0.5 mL, 1/2" needle). All study animals have ad libitum access to clean, fresh water throughout the remaining blood collection period.
  • Serial blood samples (2.0 mL each) are collected from each animal at the following time points: -30, -20 (then immediately Fed), 0 (just before dose), 5, 10, 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 240, and 360 minutes following the SC dosing.
  • Blood samples (anticoagulant: none [serum]) were maintained at ambient temperature for at least 30 minutes but no more than 2 hours to allow for clotting. Serum is then separated by centrifugation and divided into two aliquots and stored frozen at approximately -70 °C. Aliquots are shipped on dry ice by a next day shipping service.
  • Serum insulin concentrations are determined using a competitive radioimmunoassay (RIA), as described above. Data are analyzed utilizing non-compartmental pharmacokinetic analysis using Phoenix WinNonLin 6.3, as described above. Serum glucose concentrations are determined using an automated Cobas c311 Clinical Chemistry Analyzer (Roche Diagnostics, Indianapolis, Indiana).
  • Serum glucose results are given in Table 6 below. Table 6. Serum glucose results (mg/dL). HUMALOG Reference Formulation C insulin lispro + 5 mM triphosphate Formulation D insulin lispro + 10 mM triphosphate Formulation E insulin lispro + 20 mM triphosphate Time (min) Average St. dev. Average St. dev. Average St. dev. Average St. dev. Average St. dev.
  • PK parameters as a function of triphosphate concentration are given in Table 7 below. Table 7.
  • Fifteen diabetic (Alloxan induced), castrated, male Yucatan miniature swine with previously fitted vascular access ports are used to study the effect of triphosphate on the serum glucose and serum insulin time action profiles of different commercial insulins. Housing and nutrition of the animals and shipment and storage of the test and control articles are as described above in Studies 1 and 2.
  • Test articles are formulated by adding sufficient triphosphate to commercial vials of HUMULIN-RG, NOVOLOG ® and APIDRA ® to reach a concentration of 20 mM triphosphate. Note that the concentrations of other ingredients listed in the table below reflect the concentrations of those ingredients in the commercial vials of those products; the concentrations have not been adjusted to account for the slight dilution resulting from the addition of triphosphate. Table 8. Compositions of test and control articles.
  • Formulation Composition HUMALOG 3.5 mg/mL insulin lispro 7 mM sodium phosphate, pH 7.4 0.3 mM Zn 16 mg/mL glycerin 3.15 mg/mL m-cresol
  • Formulation F NOVOLOG + 20 mM triphosphate 100 Units/mL insulin aspart 19.6 mcg/mL zinc 16 mg/mL glycerin 1.50 mg/mL phenol 1.72 mg/mL m-cresol 1.25 mg/mL disodium hydrogen phosphate dehydrate 0.58 mg/mL sodium chloride 20 mM sodium triphosphate
  • Formulation G APIDRA + 20 mM triphosphate 100 units/mL insulin glulisine 3.15 mg/mL m-cresol 6 mg/mL tromethamine, 5 mg/mL sodium chloride 0.01 mg/mL polysorbate 20 20 mM sodium triphosphate
  • Formulation H HUMULIN + 20 mM triphosphate 100 units/mL insulin 16
  • the study is a four-way cross over design allowing for each individual animal to receive each of the three test articles and the control by dosing one test article on each study date (4 dates each, 7 days apart). Animals are prepared for the study as described above with respect to Studies 1 and 2.
  • Serum glucose concentrations are determined using an automated AU480 Clinical Chemistry Analyzer (Beckman Coulter). Serum glucose results (mg/dL) are given in Table 9 below. Table 9. Serum glucose results (mg/dL).
  • HUMALOG Formulation F HUMULIN + 20 mM triphosphate Formulation G: APIDRA + 20 mM triphosphate Formulation H: NOVOLOG + 20 mM triphosphate Time (min) Average St. dev. Average St. dev. Average St. dev. Average St. dev. dev.
  • Serum insulin concentrations are determined using a competitive radioimmunoassay (RIA), as described above with respect to Studies 1 and 2. Data are analyzed utilizing non-compartmental pharmacokinetic analysis using Phoenix WinNonLin. Pharmacokinetic parameters as a function of triphosphate concentration are given in Table 10 below. Table 10. PK data. Abbreviations: Tmax - time at maximal insulin concentration, Cmax - maximal insulin concentration, AUC INF - area under the curve from 0 to infinity, CL/F - clearance/bioavailability.
  • Formulation Tmax (min) Cmax (nM) AUC INF (min ⁇ nM) CL/F (mL/min/kg) HUMALOG N 13 Mean ⁇ SE 58.8 ⁇ 7.49 1.12 ⁇ 0.176 129 ⁇ 9.27 9.88 ⁇ 0.669 Median 60 1.00 120 9.99
  • Formulation F: HUMULIN + 20 mM triphosphate N 14 Mean ⁇ SE 22.5 ⁇ 9.55 1.45 ⁇ 0.230 173 ⁇ 14.6 7.48 ⁇ 0.527 Median 7.50 1.12 159 7.54
  • Formulation G: APIDRA + 20 mM triphosphate N 15 Mean ⁇ SE 17.7 ⁇ 4.02 1.65 ⁇ 0.196 166 ⁇ 11.7 7.75 ⁇ 0.527 Median 10.0 1.52 153 7.85
  • Formulation H: NOVOLOG + 20 mM triphosphate N 14 Mean ⁇ SE 27.9 ⁇ 10.8 1.10 ⁇ 0.111 121 ⁇ 12.7 10.9 ⁇ 0.784 Median 12.5 0.980
  • the PK/PD data demonstrate that the use of triphosphate in formulations of various commercial insulins accelerated time-action and reduced Tmax as compared with HUMALOG with no triphosphate. All formulations containing 20 mM triphosphate caused faster Tmax as compared with HUMALOG alone. Formulations containing APIDRA and HUMULIN with 20 mM triphosphate caused higher Cmax as compared with HUMALOG alone.
  • a clinical study is conducted to study the pharmacokinetic and pharmacodynamic effects of compositions of the present invention.
  • the study is designed as a 5-period crossover study to compare the effects following subcutaneous (SC) doses of 4 formulations containing different concentrations of triphosphate with insulin lispro, as compared to a formulation of insulin lispro containing no triphosphate.
  • Test articles are formulated by adding sufficient amounts of triphosphate and magnesium chloride to the U200 commercial formulation of insulin lispro to reach the concentrations indicated in Table 11 below: Table 11. Compositions of test and control articles.
  • the U-200 HUMALOG formulation to which triphosphate and MgCh are added to create the test articles also contains 5 mg/mL tromethamine, 16 mg/mL glycerin, 3.15 mg/mL m-cresol and 0.046 mg/mL Zn 2+ .
  • Formulation Name Formulation Composition HUMALOG 100 units/mL insulin lispro 7 mM sodium phosphate 0.3 mM Zn 16 mg/mL glycerin 3.15 mg/mL m-cresol Formulation I + 10 mM triphosphate Formulation J + 20 mM triphosphate Formulation K + 30 mM triphosphate Formulation L + 30 mM triphosphate + 7.5 mMMgCh
  • Healthy subjects are enrolled and each subject is randomized to a treatment sequence, comprising single 15 unit SC doses of insulin lispro alone and a single 15 insulin unit SC dose of each of the test formulations.
  • a minimum of 3 days is required between dosing occasions for an individual subject.
  • Plasma samples are collected at multiple time points to determine the serum concentrations of insulin lispro over time. Serum concentrations of insulin lispro are measured using a validated enzyme-linked immunosorbent assay method specific for insulin lispro. Pharmacokinetic analyses are conducted using standard noncompartmental methods of analysis using Phoenix ® version 7.0 (or higher) and S-PLUS ® software (version 8.2). Free serum insulin lispro concentrations are used to calculate pharmacokinetic parameters. Results are provided in Table 12 below. Table 12. PK data.
  • LS - least squares CI - confidence interval
  • T onset - time to onset of insulin appearance early 50% T max - time to early half-maximal drug concentration
  • AUC (0-15min) area under the curve from time zero to 15 minutes
  • AUC(o- 30min) area under the curve from time zero to 30 minutes
  • late 50% t max - time to late half-maximal drug concentration P-value for all test articles compared to Humalog control ⁇ .0001.
  • a 5-hour euglycemic glucose clamp is conducted in each period to allow an assessment of glucodynamic response to each treatment.
  • the glucose infusion rate (GIR) over time is used as a measure of insulin effect.
  • a locally weighted scatterplot smoothing (LOESS) function is applied to all individual GIR versus time profiles in each treatment group and/or period using S-PLUS software version 8.2. The fitted data for each subject are used to calculate glucodynamic parameters.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Engineering & Computer Science (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Endocrinology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Zoology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dermatology (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Obesity (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
EP18735017.8A 2017-06-01 2018-05-31 Rapid-acting insulin compositions Active EP3630166B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201762513645P 2017-06-01 2017-06-01
PCT/US2018/035261 WO2018222787A1 (en) 2017-06-01 2018-05-31 Rapid-acting insulin compositions

Publications (2)

Publication Number Publication Date
EP3630166A1 EP3630166A1 (en) 2020-04-08
EP3630166B1 true EP3630166B1 (en) 2022-04-06

Family

ID=62779004

Family Applications (1)

Application Number Title Priority Date Filing Date
EP18735017.8A Active EP3630166B1 (en) 2017-06-01 2018-05-31 Rapid-acting insulin compositions

Country Status (25)

Country Link
US (1) US11207384B2 (ar)
EP (1) EP3630166B1 (ar)
JP (1) JP6920471B2 (ar)
KR (2) KR20190140048A (ar)
CN (1) CN110662551B (ar)
AU (1) AU2018275545B2 (ar)
BR (1) BR112019022212A2 (ar)
CA (1) CA3065308C (ar)
CL (1) CL2019003336A1 (ar)
CO (1) CO2019013251A2 (ar)
CR (1) CR20190522A (ar)
DO (1) DOP2019000300A (ar)
EA (1) EA201992351A1 (ar)
EC (1) ECSP19085451A (ar)
ES (1) ES2912162T3 (ar)
IL (1) IL270975B2 (ar)
JO (1) JOP20190277B1 (ar)
MA (1) MA50496A (ar)
MX (1) MX2019014195A (ar)
NZ (1) NZ758298A (ar)
PE (1) PE20200017A1 (ar)
PH (1) PH12019502677A1 (ar)
SA (1) SA519410672B1 (ar)
UA (1) UA126450C2 (ar)
WO (1) WO2018222787A1 (ar)

Family Cites Families (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0018609B1 (de) 1979-04-30 1983-09-21 Hoechst Aktiengesellschaft Gegen Denaturierung beständige, wässrige Protein-Lösungen, Verfahren zu ihrer Herstellung und ihre Verwendung
FI78616C (fi) 1982-02-05 1989-09-11 Novo Industri As Foerfarande foer framstaellning av en foer infusionsaendamaol avsedd stabiliserad insulinloesning, som har en foerhoejd zinkhalt.
PH25772A (en) 1985-08-30 1991-10-18 Novo Industri As Insulin analogues, process for their preparation
WO1988006599A1 (en) 1987-02-25 1988-09-07 Novo Industri A/S Novel insulin derivatives
JPH04502465A (ja) 1988-12-23 1992-05-07 ノボ　ノルディスク　アクティーゼルスカブ ヒトインシュリン類似物質
US5716927A (en) 1988-12-23 1998-02-10 Novo Nordisk A/S Insulin analogs having a modified B-chain
US5547942A (en) 1994-01-04 1996-08-20 Rapaport; Eliezer Method of treatment of diabetes mellitus by administration of adenosine 5'-t
US5474978A (en) 1994-06-16 1995-12-12 Eli Lilly And Company Insulin analog formulations
US5912014A (en) 1996-03-15 1999-06-15 Unigene Laboratories, Inc. Oral salmon calcitonin pharmaceutical products
US5866538A (en) 1996-06-20 1999-02-02 Novo Nordisk A/S Insulin preparations containing NaCl
AUPO066096A0 (en) 1996-06-26 1996-07-18 Peptide Delivery Systems Pty Ltd Oral delivery of peptides
WO1999034821A1 (en) 1998-01-09 1999-07-15 Novo Nordisk A/S Stabilised insulin compositions
WO2000043034A2 (en) 1999-01-26 2000-07-27 Eli Lilly And Company Monodisperse hexameric acylated insulin analog formulations
JP2003514014A (ja) 1999-11-15 2003-04-15 ティー ガンガル，ハナマラディ 静脈注入のためのブドウ糖およびインスリン含有液体配合物
US7084126B1 (en) 2000-05-01 2006-08-01 Healthpartners Research Foundation Methods and compositions for enhancing cellular function through protection of tissue components
US20020141946A1 (en) 2000-12-29 2002-10-03 Advanced Inhalation Research, Inc. Particles for inhalation having rapid release properties
DE10114178A1 (de) 2001-03-23 2002-10-10 Aventis Pharma Gmbh Zinkfreie und zinkarme Insulinzubereitungen mit verbesserter Stabilität
DE10227232A1 (de) 2002-06-18 2004-01-15 Aventis Pharma Deutschland Gmbh Saure Insulinzubereitungen mit verbesserter Stabilität
DE10351594A1 (de) * 2003-11-05 2005-06-16 Tecpharma Licensing Ag Vorrichtung für die Verabreichung eines injizierbaren Produkts
US20080090753A1 (en) 2004-03-12 2008-04-17 Biodel, Inc. Rapid Acting Injectable Insulin Compositions
EP1740154B1 (en) 2004-03-12 2009-06-17 Biodel, Inc. Insulin compositions with improved absorption
US8084420B2 (en) 2005-09-29 2011-12-27 Biodel Inc. Rapid acting and long acting insulin combination formulations
US20070086952A1 (en) 2005-09-29 2007-04-19 Biodel, Inc. Rapid Acting and Prolonged Acting Inhalable Insulin Preparations
CN101754747A (zh) 2007-06-05 2010-06-23 Paka肺部医药公司 用于向肺脏递送药物的方法以及组合物
WO2008152106A1 (en) 2007-06-13 2008-12-18 Novo Nordisk A/S Pharmaceutical formulation comprising an insulin derivative
TWI394580B (zh) 2008-04-28 2013-05-01 Halozyme Inc 超快起作用胰島素組成物
US9060927B2 (en) 2009-03-03 2015-06-23 Biodel Inc. Insulin formulations for rapid uptake
FR2943538B1 (fr) 2009-03-27 2011-05-20 Adocia Formulation a action rapide d'insuline recombinante humaine
US20120094902A1 (en) * 2009-03-27 2012-04-19 Adocia Fast-acting insulin formulation
EP2590667A4 (en) 2010-07-07 2013-11-27 Biodel Inc COMPOSITIONS AND METHODS FOR THE MODULATION OF PHARMACOKINETICS AND PHARMACODYNAMIC INSULIN
JP5890516B2 (ja) 2011-06-17 2016-03-22 ハロザイム インコーポレイテッド ヒアルロナン分解酵素を用いる連続的皮下インスリン注入方法
US9993529B2 (en) 2011-06-17 2018-06-12 Halozyme, Inc. Stable formulations of a hyaluronan-degrading enzyme
US20130231281A1 (en) 2011-11-02 2013-09-05 Adocia Rapid acting insulin formulation comprising an oligosaccharide
ES2749620T3 (es) 2011-12-30 2020-03-23 Halozyme Inc Variantes de polipéptidos de PH20, formulaciones y usos de los mismos
US9381247B2 (en) 2012-04-16 2016-07-05 Biodel Inc. Magnesium compositions for modulating the pharmacokinetics and pharmacodynamics of insulin and insulin analogs, and injection site pain
US9399065B2 (en) 2012-04-16 2016-07-26 Biodel Inc. Magnesium compositions for modulating the pharmacokinetics and injection site pain of insulin
BR112015010799B1 (pt) 2012-11-13 2023-01-17 Adocia Composição em solução aquosa, e, formulação farmacêutica
US20150065423A1 (en) 2013-08-30 2015-03-05 Perosphere, Inc. Rapid acting injectable formulations
CN106102763A (zh) 2014-01-13 2016-11-09 塞尔玛琳糖尿病有限责任公司 速效胰岛素制剂和药物递送系统
WO2015120457A1 (en) 2014-02-10 2015-08-13 Biodel Inc. Stabilized ultra-rapid-acting insulin formulations
JO3624B1 (ar) 2014-05-08 2020-08-27 Lilly Co Eli تركيبات إنسولين سريعة المفعول
US9795678B2 (en) * 2014-05-14 2017-10-24 Adocia Fast-acting insulin composition comprising a substituted anionic compound and a polyanionic compound
TW201630622A (zh) * 2014-12-16 2016-09-01 美國禮來大藥廠 速效胰島素組合物
EP3328388B1 (en) 2015-07-28 2023-12-27 Eli Lilly and Company A pharmaceutical preparation for improving absorption and postprandial hypoglycemic action of insulin
JO3749B1 (ar) 2015-08-27 2021-01-31 Lilly Co Eli تركيبات إنسولين سريعة المفعول
GB201607918D0 (en) * 2016-05-06 2016-06-22 Arecor Ltd Novel formulations
WO2018023060A1 (en) 2016-07-29 2018-02-01 Massachusetts, University Of Small molecule inhibitors for transcription factors
GB201707188D0 (en) 2017-05-05 2017-06-21 Arecor Ltd Novel formulations
GB201707189D0 (en) 2017-05-05 2017-06-21 Arecor Ltd Novel formulations

Also Published As

Publication number Publication date
IL270975B2 (en) 2024-02-01
SA519410672B1 (ar) 2022-06-16
IL270975A (en) 2020-01-30
KR102342865B1 (ko) 2021-12-24
BR112019022212A2 (pt) 2020-05-12
ES2912162T3 (es) 2022-05-24
CA3065308C (en) 2022-05-17
AU2018275545A1 (en) 2019-10-31
MX2019014195A (es) 2020-01-27
EP3630166A1 (en) 2020-04-08
MA50496A (fr) 2020-09-09
KR20190140048A (ko) 2019-12-18
JOP20190277A1 (ar) 2019-11-28
CO2019013251A2 (es) 2020-01-17
CR20190522A (es) 2020-01-15
KR20210106029A (ko) 2021-08-27
JP2020522470A (ja) 2020-07-30
CN110662551A (zh) 2020-01-07
ECSP19085451A (es) 2019-12-27
AU2018275545B2 (en) 2021-02-04
IL270975B1 (en) 2023-10-01
JP6920471B2 (ja) 2021-08-18
EA201992351A1 (ru) 2020-03-26
US20200078446A1 (en) 2020-03-12
PH12019502677A1 (en) 2020-06-08
DOP2019000300A (es) 2019-01-15
NZ758298A (en) 2022-11-25
CL2019003336A1 (es) 2020-05-15
US11207384B2 (en) 2021-12-28
CN110662551B (zh) 2023-07-18
JOP20190277B1 (ar) 2023-09-17
CA3065308A1 (en) 2018-12-06
WO2018222787A1 (en) 2018-12-06
UA126450C2 (uk) 2022-10-05
PE20200017A1 (es) 2020-01-06

Similar Documents

Publication Publication Date Title
EP3536380B1 (en) Rapid-acting insulin compositions
US11872266B2 (en) Rapid-acting insulin compositions
EP3340966B1 (en) Rapid-acting insulin compositions
EP3630166B1 (en) Rapid-acting insulin compositions
EA042403B1 (ru) Быстродействующая композиция инсулина

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20200102

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 40016003

Country of ref document: HK

RAV Requested validation state of the european patent: fee paid

Extension state: MA

Effective date: 20200102

Extension state: MD

Effective date: 20200102

Extension state: TN

Effective date: 20200102

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20201221

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTG Intention to grant announced

Effective date: 20211103

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 1480673

Country of ref document: AT

Kind code of ref document: T

Effective date: 20220415

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602018033379

Country of ref document: DE

REG Reference to a national code

Ref country code: NL

Ref legal event code: FP

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2912162

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20220524

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG9D

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20220401239

Country of ref document: GR

Effective date: 20220707

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 1480673

Country of ref document: AT

Kind code of ref document: T

Effective date: 20220406

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220406

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220808

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220706

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220406

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220406

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220406

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220706

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220406

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220406

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220406

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220406

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220806

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602018033379

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220406

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220406

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220406

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220406

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20220531

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220406

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220406

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220406

VS25 Lapsed in a validation state [announced via postgrant information from nat. office to epo]

Ref country code: MD

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220406

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20230110

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220406

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20220531

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220406

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230412

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20230420

Year of fee payment: 6

Ref country code: FR

Payment date: 20230420

Year of fee payment: 6

Ref country code: ES

Payment date: 20230601

Year of fee payment: 6

Ref country code: DE

Payment date: 20230419

Year of fee payment: 6

Ref country code: CH

Payment date: 20230602

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: TR

Payment date: 20230428

Year of fee payment: 6

Ref country code: GR

Payment date: 20230420

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20230419

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20230420

Year of fee payment: 6

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220406

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220406

VS25 Lapsed in a validation state [announced via postgrant information from nat. office to epo]

Ref country code: MA

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220406

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20240418

Year of fee payment: 7